Is ALK p.Gln1388= (c.4164G>A) pathogenic?

ALK p.Gln1388= (c.4164G>A) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0516%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Gln1388= (c.4164G>A)?

ALK p.Gln1388= (c.4164G>A) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Gln1388= (c.4164G>A) in the general population?

ALK p.Gln1388= (c.4164G>A) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

ALK p.Gln1388=

c.4164G>A · rs200902932 · VCV567316

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Pangolin	Δ0.34	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% South Asian · 47/91,046 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00298% 48/1,611,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,937
Remaining individualsnot grpmax-eligible	0.0016%	62,402

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALK
Protein: p.Gln1388=
Coding: c.4164G>A
MANE Select: NM_004304
dbSNP: rs200902932
Type: single nucleotide variant
Location: chr2:29196770 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1388: an α-helix; the protein kinase domain

Full ALK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Gln1388His Uncertain significance ★★ ⚠ same residue
ALK p.Gln1388Arg Uncertain significance ★ ⚠ same residue
ALK p.Gln1388Glu Uncertain significance ★ ⚠ same residue
ALK p.Gln1388Ter Uncertain significance ★ same residue
ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>A Uncertain significance ★★ same condition
ALK c.1155-3C>T Uncertain significance ★★ same condition
ALK c.1282+3A>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alk-p-gln1388 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown